Abstract
Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α’s activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.
Original language | English (US) |
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Pages (from-to) | 885-895.e7 |
Journal | Molecular cell |
Volume | 76 |
Issue number | 6 |
DOIs | |
State | Published - Dec 19 2019 |
Keywords
- KDM3A
- PGC-1α
- hypoxia
- mitochondrial biogenesis
- monomethylation
- oxygen sensing
- tumorigenesis
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
MD Anderson CCSG core facilities
- Functional Genomics Core
- High Resolution Electron Microscopy Facility